Pancreatic cancer is the fourth leading cause of cancer-related death in the United States. There is a clear need for more effective therapies to treat deadly pancreatic cancer disease. MicroRNAs (miRNA or miR) are a large group of short, noncoding RNAs that control posttranscriptional gene expression in human cells, and there is increasing evidence for the existence of tumor suppressive and oncogenic miRNAs deregulated in human carcinomas. A tumor suppressor miRNA down-regulated in cancerous tissues may be reintroduced into cancer cells via a novel approach, known as miRNA replacement therapy, to block tumor growth. We have identified a tumor suppressor miRNA, miR-1291, that is expressed at reduced levels in human pancreatic ductal adenocarcinoma (PDAC) compared to normal pancreatic ductal tissue. The reintroduction of miR-1291 mimics into PDAC cells induces cancer cell cycle arrest and the suppression of xenograft pancreatic tumor growth. Given the tumor suppressive role for miR-1291 that exhibits a loss-of-function in PDAC, this STTR Phase I project is proposed to critically assess a new miR-1291 replacement therapy technology to treat pancreatic cancer. Specifically, Aim 1 is to demonstrate the effectiveness of miR-1291 replacement therapy in control of pancreatic tumor growth in clinically relevant animal models, and Aim 2 is to establish the pharmacokinetic and safety profiles of miR-1291 complexed in clinically relevant drug delivery system. Successful completion of Phase I will identify a therapeutic miR-1291 formulation that will be the subject of pre-clinical development in preparation of an IND submission in Phase II.